title: Synthesis and structure-activity relationships of selective norepinephrine reuptake inhibitors (sNRI) with improved pharmaceutical characteristics.
abstract: The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pontillo
authors.forename: Dongpei
authors.initials: D
authors.lastname: Wu
authors.forename: Brett
authors.initials: B
authors.lastname: Ching
authors.forename: Sarah
authors.initials: S
authors.lastname: Hudson
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Genicot
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Gao
authors.forename: Todd
authors.initials: T
authors.lastname: Ewing
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fleck
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gogas
authors.forename: Anna
authors.initials: A
authors.lastname: Aparicio
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Warren S
authors.initials: WS
authors.lastname: Wade
mesh_terms: D000069445:Atomoxetine Hydrochloride; D020650:Combinatorial Chemistry Techniques; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D015195:Drug Design; D006801:Humans; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D011437:Propylamines / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D007189:Indans; D014179:Neurotransmitter Uptake Inhibitors; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride; D009638:Norepinephrine